ABSTRACT For largely unknown reasons, aging is accompanied by progressive loss of skeletal muscle mass, strength, function, and regenerative capacity.1 By the time US adults reach 60 years of age, 30% will suffer from sarco- penia, characterized by clinically recognizable chronic muscle degeneration manifesting as extreme fatigue, weakness, and greatly reduced physical activity.3-5 This condition typically progresses to highly debilitating frailty syndrome. Treating this age-associated chronic disease is critical to avoid significant decreases in the quality of life among older adults. An estimated 15M US adults suffer with sarcopenia, and this chronic disease will become increasingly pervasive and an ever greater healthcare problem as the number of older Americans steadily increase over the next 30 years. Given the scope and impact of this chronic disease, there is a clear unmet need for drugs that slow, stop, or reverse sarcopenia and thus significantly improve the quality of life for aging Americans with deteriorating muscle function. Although the etiology of sarcopenia is not well understood, current research suggests that a critical deter- minant of sarcopenia is muscle stem cell (muSC) senescence. A working mechanism for the development of muSC senescence is as follows: as muscle cells age, they progressively develop increased expression and/or activity of nicotinamide N-methyltransferase (NNMT), which results in lowered intracellular NAD+ levels, re- duced SIRT1 activity, increased premature differentiation of muSCs, and elevated muSC senescence that ul- timately interferes with muSC-mediated muscle growth and homeostasis. Recently, we developed small molecules that selectively inhibit NNMT, activate the NAD salvage pathway, and increase intracellular levels of NAD+. Our lead series of NNMT inhibitors have excellent physicochemical properties (e.g., high solubility, stability, permeability), high selectivity, clean off-target pharmacological profile, promising pharmacokinetic profile (e.g., high oral bioavailability, 20-hr half-life), and no apparent signs of early toxicity/adverse indications. Our preliminary in vivo studies have demonstrated that NNMT inhibitors can increase muSC activity and re- generative capacity, enhance muscle fiber growth, and improve muscle mitochondrial respiratory capacity and function in aged mice. Based on these promising results we hypothesize that small molecule NNMT inhibi- tors can safely normalize defects in aged muscle pathophysiology and mitigate/reverse sarcopenia. This hypothesis will be tested using translationally-relevant in vivo models for muscle regeneration, repair, and function and in vitro and in vivo models for drug safety. Upon successful completion of this project, a drug can- didate will be identified that could advance to IND-directed preclinical studies. The assembled project team has extensive expertise ranging from drug development to in vivo muscle function assessment, and is eminently qualified to perform the described studies and successfully complete this project.